Sudden cardiac death is a major cause of death around the world, with approximately 400,000 sudden deaths per year in the United States, more than are attributed to lung cancer, breast cancer, or AIDS. It is often caused by ventricular fibrillation (VF) and ventricular tachycardia (VT). VF is the most frequent mechanism of sudden death. Implantable cardiac defibrillators (ICDs) have become the standard of care for patients at risk for sudden death following two decades of advancement in ICD therapy. The most common strategy for terminating VF is with a large electric shock by ICDs. Despite the proven efficacy of ICDs in saving lives, at least three major issues have been linked with their high voltage (HV) shocks. First, high voltage shocks produce substantial pain, which is often associated with anxiety, fear, depression, and reduced quality of life. Secondly, an estimated 20 percent of patients with ICDs may experience inappropriate shocks within three years of implant in response to a non-lethal arrhythmia or electrical noise within the device. In the primary prevention era, inappropriate shocks are even more troublesome, since appropriate shocks are decreasing in incidence; shocks are being delivered to patients with no history of symptomatic arrhythmias. Thirdly, shocks have been associated with an increased risk of heart failure and death. A new report by Sweeney, et al clearly demonstrated that shocked patients have substantially higher ventricular arrhythmia episode burden and poorer survival compared with anti-tachycardia pacing-only-treated patients. The virtual electrode polarization (VEP) concept has been proposed as a mechanism sustaining atrial fibrillation (AF) and demonstrated in experimental optical mapping of transmembrane potential studies in vitro and in vivo. Recent canine results have revealed that multiple-stage therapy (MST) significantly lowers the energy required for atrial defibrillation. Specifically, the three-stage therapy significantly lowers the energy for cardioversion of AF by application of three different stages of therapy, which we mechanistically relate to the: (1) unpinning of wave fronts that maintain AF, (2) prevent repinning of wave fronts to tissue heterogeneities such as scar, and (3) annihilation of remaining wave fronts. We hypothesize that internal ventricular defibrillation will be effective using a mult-stage algorithm that will require much less energy level than the current single biphasic shock. To evaluate this novel method, we propose to develop an efficient external defibrillation system based on the VEP concept incorporating two different engineering approaches; 1) variable pulse modulation and 2) single FET power amplifier system. We will then test in an acute canine study to compare performance with a single fixed vector versus a variable vector. It is anticipated that the proposed new study will provide fundamentally important insights into the hypothesis that multiple phased low-energy shocks can safely achieve internal ventricular defibrillation. We expect the study is a big step forward from the VEP and unpinning theory to ventricular defibrillator clinical development. If the enhanced system is effective and safe for ventricular defibrillation, it should advance commercial product development of low-energy multiple pulse implantable defibrillator devices and will also encourage a higher percentage of eligible patients to consider this life-saving treatment. PUBLIC HEALTH RELEVANCE: Sudden cardiac death is a major cause of death around the world, with approximately 400,000 sudden deaths per year in the United States. Ventricular fibrillation (VF) is the most frequent cause. The most common strategy for terminating VF is with a single, large, biphasic electric shock by an implantable cardiac defibrillator (ICD). Despite ther effectiveness, there have been increasing concerns with current ICD design, due to cardiac tissue damage likely induced by high voltage shocks, pain caused by inappropriate shocks, and short battery life. Currently, only about 1/3 of the eligible patient population has a defibrillato implanted. Redesign and optimization of shock waveforms is critical for developing a low-energy defibrillator delivering multistage therapy and incorporating variable pulse-shaped waveforms that will be more acceptable to patients and clinicians. The current global market for ICDs is approximately $6.6 billion and is projected to grow to $7.8 billion by 2014, offering opportunities to break into this market with disruptive technology.